The effect of TYB-3823, a new antiarrhythmic drug, on sodium current in isolated cardiac cells

Enzymatically dispersed single cells from rabbit ventricle were voltage clamped using the suction pipette method to investigate whether in isolated cardiac cells a recently described slow inward current (IEX) due to the electrogenic Na+-dependent Ca2+ extrusion also underlies a transient inward current (ITI), which can trigger certain cardiac arrhythmias. The cells were held at -40 mV to inactivate the fast sodium current. After depolarizing pulses (to 0 or +10 mV for 50 to 200 ms), slow inward "tail" currents were consistently recorded. Previous results indicate that this tail current IEX is generated by the Na+-Ca2+ exchanger. After loading the cells with Ca2+ by blocking the Na+-K+ pump [either with strophanthidin (10(-5) M) treatment or by reducing external K+ to 1 mM or less], ITIS appeared. These were usually spontaneous but occasionally were time locked to the clamp pulses. It was possible to separate IEX and ITI by a variety of methods. These include the following. 1) Different stimulation protocols; repolarizing to more negative potentials augmented IEX and decreased or eliminated ITI. Increasing the rate of stimulation diminished IEX and increased ITI. 2) Pharmacological methods; adding BaCl2 (0.5-2.0 mM) or caffeine (5-10 mM) decreased IEX but abolished ITI. The findings suggest that different mechanisms regulate these two currents.

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Electrophysiology of the Sodium-Potassium-ATPase in Cardiac Cells

Physiological Reviews ◽

10.1152/physrev.2001.81.4.1791 ◽

2001 ◽

Vol 81 (4) ◽

pp. 1791-1826 ◽

Cited By ~ 141

Author(s):

Helfried Günther Glitsch

Keyword(s):

Cell Membrane ◽

Potential Gradient ◽

Outward Current ◽

Pump Current ◽

Cardiac Cells ◽

Animal Cells ◽

Excitable Cells ◽

Extracellular Medium ◽

Enzymatic Isolation ◽

Isolated Cardiac Cells

Like several other ion transporters, the Na+-K+ pump of animal cells is electrogenic. The pump generates the pump current I p. Under physiological conditions, I p is an outward current. It can be measured by electrophysiological methods. These methods permit the study of characteristics of the Na+-K+ pump in its physiological environment, i.e., in the cell membrane. The cell membrane, across which a potential gradient exists, separates the cytosol and extracellular medium, which have distinctly different ionic compositions. The introduction of the patch-clamp techniques and the enzymatic isolation of cells have facilitated the investigation of I p in single cardiac myocytes. This review summarizes and discusses the results obtained from I p measurements in isolated cardiac cells. These results offer new exciting insights into the voltage and ionic dependence of the Na+-K+ pump activity, its effect on membrane potential, and its modulation by hormones, transmitters, and drugs. They are fundamental for our current understanding of Na+-K+ pumping in electrically excitable cells.

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Is there a second external lidocaine binding site on mammalian cardiac cells?

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1989.257.1.h79 ◽

1989 ◽

Vol 257 (1) ◽

pp. H79-H84 ◽

Cited By ~ 5

Author(s):

L. A. Alpert ◽

H. A. Fozzard ◽

D. A. Hanck ◽

J. C. Makielski

Keyword(s):

Binding Site ◽

Cardiac Arrhythmias ◽

Local Anesthetics ◽

Sodium Current ◽

Cardiac Cells ◽

Na Channel ◽

Functional Difference ◽

Na Channels ◽

Internal Perfusion ◽

Cardiac Purkinje Cells

Lidocaine and its permanently charged analogue QX-314 block sodium current (INa) in nerve, and by this mechanism, lidocaine produces local anesthesia. When administered clinically, lidocaine prevents cardiac arrhythmias. Nerve and skeletal muscle are much more sensitive to local anesthetics when the drugs are applied inside the cell, indicating that the binding site for local anesthetics is located on the inside of those Na channels. Using a large suction pipette for voltage clamp and internal perfusion of single cardiac Purkinje cells, we demonstrate that a charged lidocaine analogue blocks INa not only when applied from the inside but also from the outside, unlike noncardiac tissue. This functional difference in heart predicts that a second local anesthetic binding site exists outside or near the outside of cardiac Na channels and emphasizes that the cardiac Na channel is different from that in nerve.

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